21st Century

“Fits”Alexandre J. Lockfeld, M.D.

Clinical Neuroscience Practice 2010

18 May, 2010 Eugene, Oregon

Current Disclosures:

Alexandre J. Lockfeld, M.D.Adult Neurology and Epilepsy

Speaker‟s Bureau/Consultant: UCB, Inc.[ Keppra ® (levetiracetam); Vimpat ® (lacosamide) ]

Overview

• History of Epilepsy

• Seizure and Epilepsy Classification

• Epilepsy Statistics and Risks

• Issues for Women with Epilepsy

• Diagnosis of Epilepsy

• Status Epilepticus

• Pharmacologic Treatment of Epilepsy

• Surgical Treatment of Epilepsy

A Brief History of Epilepsy

• c. 2000 BC – First written description of epilepsy on clay tablets in Babylon. Cause believed to be demons or spirits

• c.400 BC – “On the Sacred Disease” written, attributed to Hippocrates. Cause believed to be blocked air flow in veins

• 177 AD – Galen delivers lecture “On the Brain” in Rome. Maintains that seizures are caused by pathologic humors or toxins

History of Epilepsy –

Hippocrates (b. 460 B.C.)On the Sacred Disease

“It is thus with regard to the disease called Sacred: it appears to me to be nowise more divine nor more sacred than other diseases, but has a natural cause from which it originates like other afflictions.

Men regard its nature and cause as divine from ignorance and wonder, because it is not at all like to other diseases.”

History of EpilepsyTreatment of Epilepsy in the Middle Ages:

• Even when well intentioned, treatment was

medieval

• Included early attempts at epilepsy surgery

History of Epilepsy

The Scientific Era

• 1849 – Robert Bentley Todd develops electrical theory of epilepsy

• Bromide introduced as first true antiepileptic

• 1870 – John Hughlings Jackson describes seizure origin in cerebral cortex

• 1886 - Sir Victor Horsley publishes series of 3 cases of successful (lucky!) brain surgery to relieve epilepsy

History of Epilepsy

20th Century Advances in Epilepsy

• 1912 – Phenobarbital (PB) introduced

• 1929 – Hans Berger develops EEG

• 1938 – Phenytoin (PHT) introduced

• 1950s – Temporal lobe resections for epilepsy

• 1970s – CT scanning becomes available

• 1974 – Carbamazepine (CBZ) approved

• 1978 – Valproic Acid (VPA) licensed in U.S.

• 1980s - MRI scanning becomes available

History of Epilepsy

At the Threshold of the New Millenium:

• 1993 – Felbamate (FBM) approved in US

• 1993 – Gabapentin (GPN) approved

• 1994 – Lamotrigine (LTG) approved

• 1996 – Topiramate (TPM) approved

• 1997 – Vagus nerve stimulation approved

• 1997 – Tiagabine (TGB) approved

• 1999 – Levetiracetam (LEV) approved

• 2000 – Oxcarbazepine (OXC) approved

• 2000 – Zonisamide (ZNS) approved

History of Epilepsy

The 21st Century Begins:

• 2005 - Pregabalin (PGB) approved in US

• 2008 - Rufinamide (RFN) approved

• 2009 - Lacosamide (LCS) approved

• 2009 – Vigabatrin (VGB) approved

• 2009 - NeuroPace ® Trial published

• 2010 - Sante DBS Trial published

Seizure and Epilepsy

Classification• International League Against Epilepsy

(ILAE) classification scheme

• Latest update 2009

• Older terminology e.g. “Grand Mal” is

proving impossible to eradicate…..

Seizure Classification:

ILAE SchemePartial Seizures Generalized Seizures

Focal/local onset bilateral onset

International classification of

seizures: Partial Onset

• Simple partial seizures: conciousness

not impaired

• Complex partial seizures: with

impairment of consciousness

• Partial seizures (simple or complex)

evolving to secondarily generalized

seizures

Seizure Classification:

Complex Partial Seizures• Altered

consciousness/awareness

• Duration one half to three minutes

• May occur in clusters

• Semiology varies with site of origin

• EEG: Interictal- sharp waves or spikes; Ictal-focal or bilateral rhythmic sharp

• Amnesia

• Purposeless automatisms

• Especially when of mesial temporal lobe origin, often difficult to control

Seizure Classification:

Secondarily Generalized Seizures

• Generalized tonic

clonic seizure may be

preceded by aura or

automatisms

• Distinguishing from

primary generalized

seizures may help

guide therapy

International classification of

seizures: Generalized Seizures

• Nonconvulsive (absence) Typical (3/sec

spike and slow wave complexes on EEG)

• Atypical (<3/sec spike and slow wave

complexes on EEG)

• Convulsive Myoclonic seizures

• Clonic seizures

• Tonic seizures

• Tonic-clonic seizures

• Atonic ("drop attacks")

Seizure Classification: Generalized

Tonic-Clonic Seizure

Seizure vs. EpilepsySEIZURE:

A sudden, excessive,

rapid and local

discharge of gray matter

J. Hughlings Jackson

EPILEPSY:

Recurrent unprovoked

seizures

Epilepsy Classification

SEIZURES vs. the EPILEPSIES:

• A SEIZURE is a sign or symptom of

cerebral paroxysmal discharge.

• The EPILEPSIES are syndromes or

diseases characterized by a tendency to

have recurrent seizures along with other

clinical characteristics.

Epilepsy Classification:

MYOCLONIC EPILEPSY

• Onset childhood to young adulthood

• Sudden jerks, usually bilateral, arms>legs

• One second in duration, often multiple

• May be photic or sensory triggered

• Often maximal on awakening

• EEG: generalized polyspike-wave burst

JUVENILE MYOCLONIC EPILEPSY

• Most common myoclonic epilepsy, genes identified

• Clinical triad of

– absence seizures (in one third)

– AM myoclonic jerks (characteristic)

– tonic-clonic seizures (in majority)

• Age of onset 8 to 26 years, peak at 12-18, persists life long

• Normal neurological state and development

• EEG shows generalized polyspike/wave bursts

• AEDs: valproic acid, lamotrigine, topiramate

ABSENCE EPILEPSY

• Childhood or teenage onset

• Sudden onset, without aura, prompt offset

• Momentary loss of consciousness, eyelid flutter

• 3-15 seconds duration

• Positive Family History

• EEG – 3 Hz spike/wave

• AEDs: ethosuximide, valproic acid, lamotrigine

Fp1-F7

F7-T3

T3-T5

T5-O1

Fp2-F8

F8-T4

T4-T6

T6-O2

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Comment CLINICAL SZ EVENT Photic Start (20 Hz) Photic End (20 Hz)

Fp1-F7

F7-T3

T3-T5

T5-O1

Fp2-F8

F8-T4

T4-T6

T6-O2

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

Comment CLINICAL SZ EVENT Photic Start (20 Hz) Photic End (20 Hz)

Complex Partial Epilepsy

• Onset adolesence

through adulthood

• Most often of temporal

lobe origin

• Can be associated with

progressive hippocampal

scarring (mesial temporal

sclerosis) and cognitive

deficits

• AEDs: most any

Pyschogenic Nonepileptic

Seizures:PNES (older term

“Pseudoseizures” is discouraged)

Pyschogenic Non-Epileptic

Seizures (PNES)

• Considered a conversion disorder

• Typically, patients are not consciously manufacturing symptoms

• 70% Female preponderance

• Accounts for up to 30% of referrals for refractory epilepsy at epilepsy centers

• Most have received AEDs, some have been intubated for presumed status epilepticus

PNES

• High incidence PTSD, hx childhood sexual

abuse, other psychiatric comorbidities

• Video/EEG inpatient monitoring is highly

sensitive and specific for diagnosis

• Clinical diagnosis of seizures may be misleading

• Caution is required, since many patients exhibit

both epileptic seizures and PNES

• Psychiatric treatment is indicated but outcome is

variable.

Epilepsy Statistics

• Epilepsy and seizures affect almost 3 million

Americans of all ages, at an estimated annual

cost of $15.5 billion in direct and indirect costs.

• Approximately 200,000 new cases of seizures

and epilepsy occur each year.

• Ten percent of the American population will

experience a seizure in their lifetime.

• Three percent will develop epilepsy by age 75.

Source: Epilepsy Foundation of America http://www.epilepsyfoundation.org

Epilepsy prevalence in special

populations

• 10 percent of children with mental retardation

• 10 percent of children with cerebral palsy

• 50 percent of children with both disabilities

• 10 percent of Alzheimer patients

• 22 percent of stroke patients

• 8.7 percent of children of mothers with epilepsy

• 2.4 percent of children of fathers with epilepsy

• 33 percent of people who have had a single, unprovoked seizure

Risks of Epilepsy

• Injury from direct and indirect effects of seizures

• Sudden Unexpected Death in Epilepsy (“SUDEP”): varies with severity of epilepsy up to 10 deaths per 1000 patient-years

• Risks of treatment: reproductive and other

• Depression: Suicide risk 3 x control group in one study. FDA required warning placed on all AEDsEpilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 2007; 6(8):693-8.

• Socioeconomic marginalization due to decreased employability and socialization

• Long term cognitive declineCognitive Decline in Severe Intractable Epilepsy Epilepsia 2005 ; 46 (11) 1780 - 1787

• Bone demineralization with long term AED useEffect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58:1348-1353

Epilepsy and Driving in Oregon

• New rules adopted state-wide June 2004 (ORS 807.710 and OAR 735-074)

• Requires physicians to report persons over 14 with “Severe and Uncontrollable Impairments” not limited to epilepsy –immunity from civil liability for doing so

• Seizure control for three months on therapy generally required for driving –duty to advise?

AED Long Term Side Effects

Bone Demineralization

• Older AEDs implicated, ?new AEDs also

• Multiple mechanisms, including:

• Decreased vitamin D levels

• Reduced calcium absorption

• Hyperparathyroidism

• Calcitonin deficiency

Bone Health Treatment

Recommendations

• Screen with DEXA after 5 years of AEDs, ?at

baseline in women before starting

• All patients should receive at least 1200 mg/day

of calcium

• All patients should receive supplemental vitamin

D, at least 400 IU/day – and check levels!

• If there is evidence of osteopenia, more

aggressive treatment (biphosphonates,

calcitonin)

Issues for Women with Epilepsy

Issues for Women with Epilepsy

• Estimated 500,000 women with epilepsy of

childbearing age in US

• 3-5 births per thousand in US are to

women with epilepsy

• Some AEDs have unique toxicities for

women

• Significant interactions between AEDs and

Oral Contraceptive Pills (OCPs)

Teratogenicity of AEDs

• All older AEDs are proven teratogens

• Valproic acid causes up to 10.7% risk of

Major Congenital Malformations (MCM);

persistently lower IQ in exposed children

• Polytherapy raises birth defect incidence

• Newer AEDs are category C; data is

accumulating in AED pregnancy registries

North American AED

Pregnancy Registry

• 7,242 women enrolled since 1997

• 1-888-233-2334

• www.aedpregnancyregistry.org

• Encourage all women on AEDs to call!

NA AED Pregnancy Registry:

% MCM on Monotherapy

0

2

4

6

8

10

12

None LTG CBZ VPA

%MCM

NA AED Pregnancy Registry:

% MCM on Polytherapy

0

2

4

6

8

10

12

None CBZ+LTG CBZ+VPA LTG+VPA

NEAD Study of IQ at age 3 for

children exposed in utero (p=0.009)

86

88

90

92

94

96

98

100

102

LTG PHT CBZ VPA

IQ at 3 yrs

Recommendations for Women

• All women of childbearing potential taking

AEDs should take 1mg/day folic acid

• Folic acid 4 mg/day if AED is valproic acid

• Avoid polypharmacy and VPA if possible

• Monitor pregnancy with ultrasonography at

11 and 16 weeks; check alpha fetoprotein

• Vitamin K 10 mg/day in last trimester to

prevent newborn hemorrhagic disease

Issues for Women with Epilepsy

Special Risks of Valproic Acid -

Polycystic Ovarian Syndrome:

• Affects 7% of all reproductive age women

• Excessive androgen sensitivity

• Signs include hirsutism, obesity, acne, alopecia

and anovulatory menstrual cycles

• Metabolic findings include hyperinsulinemia,

hyperlipidemia and glucose intolerance

• VPA therapy increases risk of developing

metabolic abnormalities similar to PCOS

Recommendations for Women –

AED Effect on Oral Contraceptives

No Effect on Low

Estrogen OCPs:

• Gabapentin

• Pregabalin

• Lamotrigine (but OCP will

lower levels)

• Levetiracetam

• Lacosamide

• Tiagabine

• Zonisamide

Estrogen <35 mcg May

be Ineffective for

Contraception:

• Barbiturates

• Carbamazepine

• Oxcarbazepine

• Phenytoin

• Topiramate

Diagnosis of Epilepsy

Diagnosis of Epilepsy

• Epileptic seizures or Non-epileptic spells?

• “Not everything that shakes is epilepsy”

• Careful history taking and direct

eyewitness reports of events can make a

diagnosis or guide further testing

• Try to get description (semiology) of event,

not a lay diagnosis (e.g. “petit mal”)

Diagnosis of Epilepsy:

Consider other causes of spells• Syncope (+/- convulsion): consider cardiac

dysrythmia or neurocardiogenic syncope

• Cerebrovascular disease – “Limb Shaking TIA”

• Migraine

• Movement disorders

• Hypoxia, hypoglycemia, toxins/drugs

• Psychiatric (“Pseudoseizure” is now discouraged

– prefer “Psychogenic Non-Epileptic Seizure”)

Diagnosis of Epilepsy - EEG

• Routine (interictal) EEG usually performed, sometimes helpful in guiding therapy

• Ambulatory EEG can improve diagnosis of questionable spells, but may be difficult to interpret

• Ictal Video/EEG is the gold standard – but inter-rater reliability is not perfect

Diagnostic Imaging of Epilepsy

• MRI (3 Tesla if available) is preferred over CT, except in acute trauma, and when contraindicated

• MRI can show subtle lesions such as mesial temporal sclerosis (arrow) not apparent on CT scans

Evaluation at the Epilepsy Center

• Invasive monitoring

(depth electrodes or

subdural grids) for

presurgical workup

Magnetoencephalography (MEG)

• Promising and increasingly used in epilepsy centers

• Measures the induced magnetic fields of the brain rather than directly measuring the electrical fields

• Can non-invasively record sources of epilepsy deep in the brain

• Still rather cumbersome

Diagnostic Imaging of Epilepsy -

SPECT and SISCOM

• SPECT (Single Photon

Emission Tomography)

shows areas of hypo- or

hyper-metabolism

• Ictal SPECT: IV push of

radiolabeled tracer during

seizure

• SPECT superimposed

on MRI yields „SISCOM‟

(Subtraction Ictal SPECT

Co-registered with MRI)

Pharmacologic

Treatment of Epilepsy

Antiepileptic Drug (AED)

Selection Guidelines

• Start with a safe AED appropriate for the specific

epilepsy syndrome, as monotherapy if possible

• “Start low, go slow” if possible

• Individualize AED to patient characteristics (e.g

obese, female, elderly)

• Consider potential benefits for comorbid

conditions (e.g. migraine, mood disorder, pain)

• Consider patient compliance (prefer QD or BID

dosing) and drug interactions

AED Selection GuidelinesPrimary Generalized

Epilepsies:

• Valproic Acid

• Felbamate

• Lamotrigine

• Levetiracetam

• Topiramate

• Phenobarbital

• Zonisamide (may worsen

myoclonic epilepsies)

Partial or Secondarily

Generalized Epilepsy:

Any AED may be effective

except ethosuximide

(effective only for

absence)

*Note: carbamazepine may

worsen absence epilepsy

Benefits of AEDs for Cormorbidities

• Bipolar Disorder: VPA, CBZ, OXC, LTG

• Migraine: TPM, VPA

• Painful Neuropathy: PGB, CBZ, TPM

• Trigeminal Neuralgia: CBZ, PGB, VPA

Cognitive AED Side Effects

• All AEDs can impair cognition

• Some correlation between AED efficacy and cognition ( „strong‟ AEDs worse)

• Lamotrigine and levetiracetam in general to cause less impairment.

• Many patients have idiosyncratic cognitive AED side effects

• Some AEDs more associated with psychiatric SEs (levetiracetam, felbamate, tiagabine)

• Suicide risk warning placed on all AEDs

AED by Mechanism of Excretion: Primarily Hepatic vs. Primarily Renal

• Phenobarbital

• Phenytoin

• Carbamazepine

• Valproic Acid

• Felbamate

• Lamotrigine

• (Gapapentin)

• Pregabalin

• Levetiracetam

• Lacosamide

AED selection by

Mechanism of Action

• Controversial even among epileptologists……

AED Selection – pharmacologic

considerations

• Hepatic Enzyme inducers vs. non-inducers

• Plasma Protein binding

• Half-life

• Drug-drug interactions: note particularly

valproic acid which can markedly inhibit

lamotrigine metabolism

Pharmacogenomics

• Promising approach to choosing medication best suited to an individual

• Currently in technological infancy

• Practical application reflected in new black box labeling for carbamazepine

• Increased incidence of Stevens Johnson Syndrome in Asians with HLA-B*1502

• Testing recommended before placing individual of Asian descent on CBZ

Phenytoin Side Effects:

Expected vs. Idiosyncratic

• Ataxia, dizziness

• Gingival hyperplasia

• Hirsuitism, coarsening

of facial features

• Cerebellar

Degeneration,

peripheral neuropathy

• Rash, including

Stevens Johnson

• Hepatitis

• Other hypersensitivity

reactions

• Lupus like syndrome

• Purple Glove

Syndrome

Carbamazepine Side Effects:

Expected vs. Idiosyncratic

• Ataxia

• Diplopia

• Dizziness

• Photosensitivity

• Mild neutropenia

• Hyponatremia

• Rash, including

Stevens Johnson

• Hepatitis

• Severe Neutropenia

Valproic Acid Side Effects:

Expected vs Idiosyncratic

• Sedation

• Tremor

• Weight gain

• Change in hair growth

• Mild

thrombocytopenia

• Fulminant hepatic

failure (mostly infants)

• Pancreatitis

• Valproate

encephalopathy

Felbamate Side Effects:

Expected vs Idiosyncratic

• Sleeplessness

• Agitation

• Headache

• Loss of appetite/

• Weight loss

• Aplastic Anemia (risk

1 in 3000 – 5000)

• Fulminant Hepatic

Failure

• Psychosis

Lamotrigine Side Effects:

Expected vs. Idiosyncratic

• Sedation

• Dizziness

• Diplopia

• Headache (may

worsen pre-existing

migraines)

• Rash, including

Stevens Johnson

Syndrome

Topiramate Side Effects:

Expected vs. Idiosyncratic

• Extremity paresthesias

• Altered taste of carbonated bevs

• Mild cognitive side effects, “spaciness”

• Weight loss

• Mild metabolic acidosis, increased risk of nephrolithiasis

• Acute angle closure glaucoma

• Severe cognitive side effects “zombie”

• Severe metabolic acidosis

Pregabalin Side Effects:

Expected vs. Idiosyncratic

• Sedation

• Dizziness

• Weight Gain

• Pedal edema

• Angioedema

Levetiracetam Side Effects:

Expected vs. Idiosyncratic

• Drowsiness

• Dizziness

• Mild Irritability

• Severe Mood disorder

• Psychosis

Oxcarbazepine Side Effects:

Expected vs. Idiosyncratic

• Headache

• Dizziness

• Nausea

• Diplopia

• Hyponatremia

• Rash, including

Stevens Johnson

Syndrome

• Severe Hyponatremia

Lacosamide Side Effects:

Expected vs. Idiosyncratic

• Dizziness

• Diplopia

• Drowsiness

• Ataxia

• Prolonged P-R

interval

• Hepatitis

Dietary Therapy for Epilepsy

• Ketogenic diet has proven track record in

children with intractable epilepsy, safety

questions remain

• Now efficacy has been demonstrated in

adults

• Compliance is problematic

Status Epilepticus

• Defined as seizure activity, either

continuous or intermittent, lasting greater

than 30 minutes without return to baseline

level of consciousness

• Constitutes a medical emergency

• Can result in neuronal cell death, even if

blood pressure and oxygenation is

maintained

Status Epilepticus Subtypes

• Simple Partial

• Complex Partial

• Generalized Convulsive

• Generalized Non-convulsive

• For a patient presenting with “lights on,

nobody home”, EEG required for diagnosis

of non-convulsive status epilepticus

Status Epilepticus: Causes

• Approx 1/3 due to exacerbation of pre-

existing idiopathic epilepsy, often with

medication non compliance

• 1/3 new presentation of epilepsy without

other identified cause

• 1/3 due to other: structural,

toxic/metabolic, infectious causes

Status Epilepticus: Initial evaluation

• Rule out hypoglycemia and electrolyte

imbalance

• Rule out poisoning or overdose

(stimulants, TCAs, INH)

• Rule out drug or alcohol withdrawal

• Rule out CNS mass or infection (CT scan

and CSF examination)

Status Epilepticus:

Standard Treatment

• ABCs and maintain normothermia

• Treat any identified underlying cause

• LORAZEPAM 4mg IV over 2 minutes,

repeat if needed in 15 mins (Adults) OR

DIAZEPAM 5-10 mg IV load (Adults)

• PHENYTOIN (infuse at<50mg/min) OR

FOSPHENYTOIN (up to 150mg/min,

preferred) loading dose 15-20mg/Kg

Refractory Status Epilepticus: Old

School Approach, still standard

• Standard third line agent: PHENOBARBITAL 15-20mg/Kg IV – likely to cause respiratory depression given after benzodiazepines

• Rapid sequence intubation, EEG monitoring, ICU management as needed

• Standard IV continuous therapy: PENTOBARBITAL 12mg/kg IV load then 5mg/Kg/hr IV, follow EEG monitoring

Status Epilepticus: current trends,

(off label use, no RCT data)

• Second line use of any available IV formulated AED – VALPROIC ACID, LEVETIRACETAM, LACOSAMIDE

• Third line use of IV MIDAZOLAM 0.2mg/Kg IV load, then 0.1–0.4 mg/Kg/min drip titrated to clinical effect or EEG

• Third line use of IV PROPOFOL 2mg/Kg IV load, then 0.1 – 0.2 mg/Kg/min IV drip (caution re:acidosis with prolonged use)

Surgical Treatment

of Epilepsy

Surgical Treatment of Epilepsy

• Variety of procedures available, two devices currently awaiting approval

• Requires extensive inpatient workup

• Treatment of choice for many patients with pharmacoresistant epilepsy

• Offers chance of epilepsy remission for some refractory patients

Brain Resection Surgery

Successful Outcome Involves many steps

• Accurate diagnosis

• Appropriate patient selection

• Pre-op localization of seizure focus

• Intra-operative seizure recording and functional mapping

The Future is Here!

• Clinical trial completed of

Responsive Neuro

Stimulation (RNS)

• “Brain Defibrillator”

• Electrodes implanted into

seizure focus

• Computer senses and

delivers countershock to

stop seizure

• Currently awaiting FDA

approval

Anterior Thalamic DBS for Epilepsy

• Uses same technology as for Parkinsons

• Awaiting FDA approval

Summary

• The 20th century saw an explosion of new

antiepileptic drugs

• The 21st century will see an explosion of

high-tech implantable devices and drugs

• Best patient care still begins with a

thorough history

• Careful consideration and explanation of

risks and benefits is essential

Questions?